Methods, compounds, and compositions for the treatment of angiotensin-related diseases

Abstract

Disclosed are small molecule non-peptidic compounds, as well as methods and compositions for the treatment of angiotensin-related diseases and disorders, including cardiovascular diseases, metabolic diseases, gastrointestinal diseases, renal diseases, inflammatory/autoimmune diseases, neurological diseases, bone marrow diseases and cancer.

What is claimed is: 
     
       1. A compound having the general formula 1: 
       
         
           
           
               
               
           
         
         wherein:
 ring A is a five-membered or six-membered heteroaryl or heterocyclyl ring containing either a combination of two non-adjacent nitrogen or oxygen atoms, or a combination of three or four nitrogen or oxygen atoms; 
 ring B is a five-membered or six-membered heteroaryl ring that contains at least one nitrogen atom; 
 A 1 , A 2 , A 3 , A 4  are independently selected from a group consisting of ═N—, —C(═O)—, —C(R a )═, ═C(R b )—, —C(R c )(R d )—N(R e )—, —C(R c )(R d )—O—, and —[C(R c )(R d )] n —, wherein n is 1 or 2; 
 X 1 —X 2  is —(R 6 )C—N—, —N—C(R 6 )—, —N—N—,—N—O—, —O—N—,—N—S—or —S—N—; 
 X 3  is —(R 7 )C═C(R 8 )—, —O—, —S—, or —N(R 9 )—; 
 Z is —O—, —NH— or a bond to R 5 ; 
 R a  and R b  are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, formyl, acyl, acylamido and carboxy, 
 or R a  and R b , together with the atoms to which they are attached, form a ring of up to 6 atoms; 
 R c  and R d  are independently selected from a group consisting of hydrogen, alkyl, aryl, and heteroaryl, 
 or R c  and R d , together with the atoms to which they are attached, form a ring of up to 6 atoms; 
 R e  is hydrogen, alkyl, aryl, heteroaryl, acyl, alkoxyacyl, aminoacyl, dialkylaminoacyl, or dialkylaminoacyl; 
 R 1 , R 3 , R 4 , R 6 , R 7 , and R 8  are independently selected from a group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylmethyl, heteroarylmethyl, fluoro, bromo, iodo, cyano, hydroxy, amino, alkylamino, alkoxy, aryloxy, alkoxyalkyl, and aryloxyalkyl; 
 R 2  is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylmethyl, heteroarylmethyl, alkoxy, trifluoromethoxy, perfluoroalkoxy, aryloxy, alkoxyalkyl, or aryloxyalkyl; 
 R 5  is alkyl, aryl, heteroaryl, hydroxyalkyl, carboxyalkyl, alkoxyalkyl, or aryloxyalkyl; and 
 R 9  is hydrogen, alkyl, aryl, heteroaryl, acyl, alkoxyacyl, aminoacyl, dialkylaminoacyl, or dialkylaminoacyl; 
 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       2. The compound of  claim 1 , wherein:
 ring A is selected from a group consisting of: 
 
       
         
           
           
               
               
           
         
         wherein:
 R 10  and R 11  are independently selected from a group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, formyl, acyl, acylamido and carboxy, 
 or R 10  and R 11 , together with ring A to which they are attached, form: 
 
       
       
         
           
           
               
               
           
         
         
           wherein
 R f , R g , R h , and R i ,are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylmethyl, heteroarylmethyl, fluoro, bromo, iodo, hydroxy, amino, alkylamino, alkoxy, aryloxy, alkoxyalkyl, and aryloxyalkyl; 
 
           R 12  is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, halo, hydroxy, hydroxyalkyl, alkoxyalkyl, alkoxy, aryloxy, or acylamido; 
           R 13  is hydrogen, alkyl, aryl or heteroaryl; 
           R 14  is hydrogen, alkyl, aryl, heteroaryl, acyl, alkoxyacyl, aminoacyl, dialkylaminoacyl, or dialkylaminoacyl; and 
         
         ring B is selected from a group consisting of: 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       3. The compound of  claim 2 , having a general formula selected from a group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       4. The compound of  claim 2 , having a general formula of 2a, 2b, 3a or 3b: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       5. The compound of  claim 2 , having the general formula of 4a, 4b, 5a, 5b, 6a or 6b: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein
 R 15  is alkyl, aryl, heteroaryl, arylmethyl, heteroarylmethyl, trifluoromethyl or pentafluoroethyl; and 
 R 16  is hydrogen, hydroxy, methoxy, alkoxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl, amino, alkylamino, or dialkylamino; 
 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       6. The compound of  claim 5 , wherein R 10 , R 11  and R 12  are hydrogen, or R 15  is trifluoromethyl, or R 16  is ethyl, or Z is selected from the group consisting of —O— and —NH—. 
     
     
       7. The compound of  claim 2 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       8. The compound of  claim 2 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       9. The compound of  claim 2 , wherein the compound is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       10. The compound of  claim 2 , wherein the compound is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       11. The compound of  claim 2 , wherein the compound is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       12. The compound of  claim 2 , wherein the compound is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       13. A pharmaceutical composition comprising a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
       14. A method for treating hypertension, myelodysplastic syndrome, diabetes, fat accumulation or breast cancer in a patient in need thereof, comprising administering to the patient an effective amount of the compound of  claim 1 , or a pharmaceutically acceptable salt thereof, to treat the hypertension, myelodysplastic syndrome, diabetes, fat accumulation or breast cancer. 
     
     
       15. The method according to  claim 14 , wherein the method is for treating hypertension. 
     
     
       16. The method according to  claim 14 , wherein the method is for treating myelodysplastic syndrome. 
     
     
       17. The method according to  claim 14 , wherein the method is for treating diabetes mellitus. 
     
     
       18. The method according to  claim 14 , wherein the method is for treating fat accumulation. 
     
     
       19. The method according to  claim 14 , wherein the method is for treating breast cancer. 
     
     
       20. The method of  claim 14 , wherein the compound has general formula of 4a, 4b, 5a, 5b, 6a or 6b: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein
 R 15  is alkyl, aryl, heteroaryl, arylmethyl, heteroarylmethyl, trifluoromethyl or pentafluoroethyl; and 
 R 16  is hydrogen, hydroxy, methoxy, alkoxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl, amino, alkylamino, or dialkylamino; 
 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       21. The method of  claim 14 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       22. The method of  claim 14 , wherein the compound is